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Smad6 determines BMP-regulated invasive behaviour of breast cancer cells in a zebrafish xenograft model
Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands.;Leiden Univ, Med Ctr, Canc Gemon Ctr Netherlands, NL-2300 RC Leiden, Netherlands..
Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands.;Leiden Univ, Med Ctr, Canc Gemon Ctr Netherlands, NL-2300 RC Leiden, Netherlands..
Leiden Univ, Med Ctr, Electron Microscopy Sect, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands..
Leiden Univ, Med Ctr, Electron Microscopy Sect, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands..
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 24968Article in journal (Refereed) Published
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Abstract [en]

The transforming growth factor-beta (TGF-beta) family is known to play critical roles in cancer progression. While the dual role of TGF-beta is well described, the function of bone morphogenetic proteins (BMPs) is unclear. In this study, we established the involvement of Smad6, a BMP-specific inhibitory Smad, in breast cancer cell invasion. We show that stable overexpression of Smad6 in breast cancer MCF10A M2 cells inhibits BMP signalling, thereby mitigating BMP6-induced suppression of mesenchymal marker expression. Using a zebrafish xenograft model, we demonstrate that overexpression of Smad6 potentiates invasion of MCF10A M2 cells and enhances the aggressiveness of breast cancer MDA-MB-231 cells in vivo, whereas a reversed phenotype is observed after Smad6 knockdown. Interestingly, BMP6 pre-treatment of MDA-MB-231 cells induced cluster formation at the invasive site in the zebrafish. BMP6 also stimulated cluster formation of MDA-MB-231 cells co-cultured on Human Microvascular Endothelial Cells (HMEC)-1 in vitro. Electron microscopy illustrated an induction of cell-cell contact by BMP6. The clinical relevance of our findings is highlighted by a correlation of high Smad6 expression with poor distant metastasis free survival in ER-negative cancer patients. Collectively, our data strongly indicates the involvement of Smad6 and BMP signalling in breast cancer cell invasion in vivo.

Place, publisher, year, edition, pages
2016. Vol. 6, 24968
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Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology
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URN: urn:nbn:se:uu:diva-297897DOI: 10.1038/srep24968ISI: 000374761100004PubMedID: 27113436OAI: oai:DiVA.org:uu-297897DiVA: diva2:944592
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Swedish Cancer Society
Available from: 2016-06-29 Created: 2016-06-28 Last updated: 2017-11-28Bibliographically approved

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ten Dijke, Peter

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